Our central hypothesis is that burn injury may result in the activation of inflammatory mechanisms and the generation of dysfunctional levels of potent mediators. In effect, an "escape from control". These mediators in turn lead to a prolonged, intensive inflammatory/hypermetabolic response, providing a self-destructive process which adds to the physical injury of the burn. We have approached burn injury as the ultimate form of "inflammatory disease". Our initial studies focused on the role of complement activation as a major pathophysiologic component of burn injury. We found that, in patients, animals and in vitro, thermal injury activated complement, generating the anaphylatoxins C5a and C3a. More recently, our efforts turned to the role of cytokines in burn injury, sepsis, and shock. We now believe there is a major link between complement activation and cytokine generation and regulation. Thus, to design therapies to ensure a optimal host response to burn injury, we propose to study various factors involved in the stimulation, regulation, and inhibition of mediators involved in burn injury, drawing on our own expertise to focus on the proinflammatory cytokines and complement. Our specific aims are to: 1) characterize the precise structure-functional relationships whereby C5a stimulates cytokinemia. We have evidence to suggest that, by understanding precisely how C5a stimulates cytokine transcription and translation, we may intervene, therapeutically in this process; 2) study cytokine stimulation by activated platelets, again with an eye towards therapy; 3) better understand the recently documented differences in initial cytokine production in pure burn injury and in endotoxemia and Gram-positive infection. We specifically believe injury "primes" cells early in injury to produce proinflammatory cytokines and that they later become "hyposensitized", adding to immune dysregulation; 4) characterize specific organ cytokine production and related dysfunction; 5) further localize this to the cellular level; 6) characterize the regulation of cytokine responses of PBMCs in burn patients and correlate these with clinical parameters; 7) study expression of IL-1 receptors by cells of burn patients, as compared to normals; 8) develop a model in rats to study specific cytokine inhibitors in burns; 9) study endogenous IL-l receptor antagonist and TNF-binding protein in burn patients and normals, to define the response and establish levels necessary for therapy; 10) determine anaphylatoxin (C3a, C5a) control of IL-1 receptor antagonist, TNF-binding protein, or the inhibitory cytokine IL-10. The intent of all of these is ultimately to better regulate the inflammatory response to the benefit of the burn patient.